A new method of gene therapy
Liver-destroying substance will be used in gene therapy
A group of scientists has proposed a new method for solving one of the problems of gene therapy – how to ensure that the main part of the work of the organ is performed by genetically modified cells. To do this with liver cells, they simply suggested destroying cells that had not undergone modification (How a liver-damaging drug may give a boost to gene therapy). The exceptional regenerative properties of the liver helped to implement such a bold idea. The experiment was conducted on laboratory mice.
Gene therapy is intended primarily for the treatment of diseases associated with mutations that prevent the production of substances necessary for the body. So, one type of hemophilia occurs due to a mutation in the gene responsible for the production of a protein called blood clotting factor IX, or Christmas factor. This protein is produced by liver cells. If the corresponding gene in these cells does not work, blood clotting is disrupted. It was the insufficient production of factor IX that was associated with hemophilia in Tsarevich Alexei Romanov.
Now scientists are using a modified adenoassociated virus (AAV) to deliver a DNA chain with a working version of this gene to liver cells. However, so far it has not been possible to make sure that patients receive a sufficient amount of factor IX. To eliminate the manifestations of hemophilia, it is necessary to raise the content of this protein to at least 12% of the normal level. But gene therapy using AAV can provide only 6% or less. At the same time, at high doses of the virus, it is necessary to use steroid drugs to combat the immune response. As a result, in most cases it is not possible to modify a sufficient number of liver cells or maintain high activity of new genes to give the right amount of factor IX.
The way out of the situation was prompted by the ability of the liver to repair itself, even after losing three-quarters of its cells. Sean Nygaard and his colleagues from the gene therapy laboratory at Oregon Health & Science University created a version of the AAV virus that not only carried a copy of the factor IX gene, as well as the gene controlling its expression, but also a DNA fragment encoding a short RNA chain that blocks an enzyme that causes DNA damage to liver cells and stopping the division when using the drug CEHPOBA. Thus, the modified cells remained resistant to CEHPOBA, and ordinary liver cells died when it was introduced into the body.
In the experiment, healthy newborn mice were injected with an appropriately prepared virus, and then the drug CEHPOBA was administered daily for a month. Other mice also received a virus with the factor IX gene, but did not receive the drug CEHPOBA. At the end of the experiment, the level of factor IX was 10-30 times higher in the body of mice injected with a liver-destroying drug.
The results of the experiment are reported in an article published by the journal Science Translational Medicine (Nygaard et al., A universal system to select gene-modified hepatocytes in vivo).
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10.06.2016